Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results

Authors

  • Sharon E. Plon,

    Corresponding author
    1. Department of Pediatrics, Baylor Cancer Genetics Clinic, Baylor College of Medicine, Houston, Texas
    2. Department of Molecular and Human Genetics, Baylor Cancer Genetics Clinic, Baylor College of Medicine, Houston, Texas
    • FACMG, MC3-3320; 6621 Fannin St., Houston, TX 77030
    Search for more papers by this author
    • Sharon E. Plon and Diana M. Eccles contributed equally to this work.

  • Diana M. Eccles,

    1. School of Medicine, University of Southampton, Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, United Kingdom
    Search for more papers by this author
    • Sharon E. Plon and Diana M. Eccles contributed equally to this work.

  • Douglas Easton,

    1. Cancer Research UK Genetic Epidemiology Unit, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom
    Search for more papers by this author
  • William D. Foulkes,

    1. Program in Cancer Genetics, Departments of Oncology and Human Genetics, McGill University, Montreal, Quebec, Canada
    Search for more papers by this author
  • Maurizio Genuardi,

    1. Medical Genetics Unit, Department of Clinical Pathophysiology, University of Florence, Florence, Italy
    2. Fiorgen Foundation for Pharmacogenomics, Sesto Fiorentino, Italy
    Search for more papers by this author
  • Marc S. Greenblatt,

    1. Department of Medicine and Vermont Cancer Center, University of Vermont College of Medicine, Burlington, Vermont
    Search for more papers by this author
  • Frans B.L. Hogervorst,

    1. DNA-Diagnostic Laboratory of the Family Cancer Clinic, Department of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands
    Search for more papers by this author
  • Nicoline Hoogerbrugge,

    1. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands
    Search for more papers by this author
  • Amanda B. Spurdle,

    1. Genetics and Population Health Division, Queensland Institute of Medical Research, Brisbane, Australia
    Search for more papers by this author
  • Sean V. Tavtigian

    1. International Agency for Research on Cancer; Lyon, France
    Search for more papers by this author

  • For the Mutation Pathogenicity Special Issue

  • The members of the Working Group are listed in the Appendix.

Abstract

Genetic testing of cancer susceptibility genes is now widely applied in clinical practice to predict risk of developing cancer. In general, sequence-based testing of germline DNA is used to determine whether an individual carries a change that is clearly likely to disrupt normal gene function. Genetic testing may detect changes that are clearly pathogenic, clearly neutral, or variants of unclear clinical significance. Such variants present a considerable challenge to the diagnostic laboratory and the receiving clinician in terms of interpretation and clear presentation of the implications of the result to the patient. There does not appear to be a consistent approach to interpreting and reporting the clinical significance of variants either among genes or among laboratories. The potential for confusion among clinicians and patients is considerable and misinterpretation may lead to inappropriate clinical consequences. In this article we review the current state of sequence-based genetic testing, describe other standardized reporting systems used in oncology, and propose a standardized classification system for application to sequence-based results for cancer predisposition genes. We suggest a system of five classes of variants based on the degree of likelihood of pathogenicity. Each class is associated with specific recommendations for clinical management of at-risk relatives that will depend on the syndrome. We propose that panels of experts on each cancer predisposition syndrome facilitate the classification scheme and designate appropriate surveillance and cancer management guidelines. The international adoption of a standardized reporting system should improve the clinical utility of sequence-based genetic tests to predict cancer risk. Hum Mutat 29(11), 1282–1291, 2008. © 2008 Wiley-Liss, Inc.

Ancillary